Postoperative delirium is a frequent complication in the elderly, with an incidence rate ranging from 10% to 70%. It is associated with several adverse outcomes, including prolonged hospitalizations, poor functional recovery, and in some cases increased mortality. Because the proportion of elderly surgical patients is increasing, it is critical to understand the pathophysiology of postoperative delirium. Several neurotransmitter systems appear to be involved in delirium, and the proposed studies will test the hypothesis that postoperative delirium is associated with changes in the expression of specific genes and proteins Identification of these genes and proteins will lead to novel strategies for diagnosing, treating, and possibly preventing postoperative delirium. The first aim will be to examine changes in gene expression in peripheral blood mononuclear cells (PBMCs) using DNA microarrays. This aim is based on our preliminary data indicating that surgery causes a twofold or greater change in the expression of 466 genes in PBMCs, with 329 getting up-regulated and 137 getting down-regulated. The magnitude of this surgery-inducing change in gene expression is unprecedented and raises the probability that some of these genes are the markers of and/or the cause of postoperative delirium. We will enroll 250 elderly patients (>65 years old) undergoing hip or knee replacement-a procedure that causes about 20% incidence of postoperative delirium-and assess postoperative delirium using a battery of instruments. Gene expression in pro- and post-surgery PBMCs from 50 delirious and 50 non-deledous patients will be determined using a DNA microarray chip containing 12,000 human genes. Statistical analysis of the gene expression data will identify the cluster of genes associated with postoperative delirium. The second specific aim will be to identify serum proteins that change with delirium by examining global protein expression using 2D-gel electrophoresis/mass spectrometry. The PI and the co-PI have assembled an interdisciplinary team with expertise in anesthesiology, bioinformatics, geriatrics, molecular pharmacology, nursing, psychiatry, psychology, orthopedic surgery, and statistics. In addition, consultants are available with expertise in delirium, DNA microarrays, and mass spectrometry. Our team is therefore in a unique position to successfully complete the proposed studies.